Process for producing aminopiperazine derivatives

ABSTRACT

A new industrial process excellent in yield and purity for preparing a compound of the formula:                    
     or a salt thereof in a less number of steps with a synthetic pathway without proceeding via nitroso compounds, 
     wherein R 1  is lower aryl, ar(lower)alkoxy or heterocyclic group, each of which may be substituted with halogen, and 
     R 2  is cyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may be substituted with halogen.

TECHNICAL FIELD

The present invention relates to a new industrial process excellent inyield and purity for producing aminopiperazine derivatives andpharmaceutically acceptable salts thereof in a less number of steps witha synthetic pathway without proceeding via nitroso compounds, and isuseful in a pharmaceutical field.

BACKGROUND TECHNOLOGY AND PROBLEM

The process for preparing aminopiperazine derivatives of the presentinvention is described in an international patent application(international publication number WO91/01979) published based on thePatent Cooperation Treaty. By the said process, however, isolation andpurification of intermediate products are not necessarily easy owing towater-solubility thereof or the like, so mass production of theaminopiperzine derivatives was difficult.

Additionally, the process for preparing aminopiperazine derivatives ofthe present invention is described in an international patentapplication (international publication number WO95/00502) publishedbased on the Patent Cooperation Treaty. However, said process had manyproblems as an industrial synthetic process because of a large number ofsteps (6 steps), use of a large amount of methylene chloride as asolvent for extraction, occurrence of carcinogenic nitroso compounds asintermediates, and the necessity for reduction reaction with metalliczinc.

CONSTITUTION OF INVENTION

One object of the present invention is to provide new processes forpreparing the aminopiperazine derivatives and pharmaceuticallyacceptable salts thereof which possess the potentiation of thecholinergic activity and are useful for treating disorders in thecentral nervous system, especially for treating amnesia, dementia,senile dementia, and the like in human being.

According to the present invention, the aminopiperazine derivatives ofthe object compound (I) or pharmaceutically acceptable salts thereof canbe prepared by the following processes.

wherein R¹ is lower alkyl, aryl, ar(lower)alkoxy or heterocyclic group,each of which may be substituted with halogen, and R² iscyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may besubstituted with halogen.

wherein R¹ is lower alkyl, aryl, ar(lower)alkoxy or heterocyclic group,each of which may be substituted with halogen, and R² iscyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may besubstituted with halogen.

In the above and subsequent descriptions of the present specification,suitable examples of the various definitions to be included within thescope of the invention are explained in detail as follows.

The term “lower” is intended to mean 1 to 6 carbon atom(s), unlessotherwise indicated.

Suitable “lower alkyl” may include a straight or branched one such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, and the like, in which the preferable one is methyl.

Suitable “aryl” may include phenyl, naphthyl, tolyl, xylyl, mesityl,cumenyl, and the like, in which the preferable one is phenyl ornaphthyl.

Suitable “ar(lower)alkoxy” may include benzyloxy, phenethyloxy,phenylpropoxy, benzhydryloxy, trityloxy, and the like.

Suitable “heterocyclic group” may include saturated or unsaturatedmonocyclic group containing at least one hetero-atom such as nitrogen,oxygen and sulfur atom.

Preferable “heterocyclic group” thus defined may be unsaturated 3 to8-membered (more preferably 5 or 6-membered) heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s), for example, pyrrolyl, imidazolyl,pyrazolyl, pyridyl, pyridyl N-oxide, dihydropyridyl, tetrahydropyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazinyl,tetrazolyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 5 nitrogenatom(s), for example, idolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;

unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl,isoxazolyl, oxadiazolyl, etc.;

saturated 3 to 8-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholino,sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl,isothiazolyl, thiadiazolyl, etc.;

unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2sulfur atom(s), for example, thienyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.;

unsaturated 3 to 8-membered heteromonocyclic group containing an oxygenatom, for example, furyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s), for example, benzofuranyl, etc., and the like.

Suitable “cyclo(lower)alkyl” may include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

Suitable “ar(lower)alkyl” may include benzyl, phenethyl, phenylpropyl,benzhydryl, trityl, and the like.

“Lower alkyl”, “aryl”, “ar(lower)alkoxy”, “heterocyclic group”,“cyclo(lower)alkyl” and “ar(lower)alkyl” described above may besubstituted with halogen [e.g. fluoro, chloro, bromo and iodo].

Pharmaceutically acceptable salts of the object compound(I) areconventional non-toxic salts and may include an acid addition salt suchas an inorganic acid addition salt (e.g. hydrochloride, hydrobromide,sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate,acetate, trifluoroacetate, maleate, tartrate, methanesulfonate,benzenesulfonate, toluensulfonate etc.); a salt with an amino acid (e.g.aspartic acid salt, glutamic acid salt, etc.); and the like.

The processes for preparing the object compound(I) are explained indetail in the following.

PROCESS 1

The compound(I) or a salt thereof can be prepared by reacting thecompound(III) or a salt thereof with the compound(II) or its reactivederivative at the carboxy group or a salt thereof.

Suitable salts of the compound(III) can be reffered to the ones asexemplified for the compound(I).

Suitable reactive derivative at the carboxy group of the compound (II)may include an ester, an acid halide, an acid anhydride, and the like.Suitable examples of the reactive derivatives may be an acid halide(e.g. acid chloride, acid bromide, etc.); a symmetrical acid anhydride;a mixed acid anhydride with an acid such as aliphatic carboxylic acid(e.g. acetic acid, pivalic acid, etc.), substituted phosphoric acid(e.g. dialkylphosphoric acid, diphenylphosphoric acid, etc.); an estersuch as substituted or unsubstituted lower alkyl ester (e.g. methylester, ethyl ester, propyl ester, hexyl ester, trichloromethyl ester,etc.), substituted or unsubstituted ar(lower)alkyl ester (e.g.benzylester, benzhydryl ester, p-chlorobenzyl ester, etc.), substituted orunsubstituted aryl ester (e.g. phenyl ester, tolyl ester, 4-nitrophenylester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphtyl ester,etc.), or an ester with N,N-dimethylhydroxylamine, N-hydroxysuccinimide,N-hydroxyphthalimide or 1-hydroxy-6-chloro-1H-benzotriazole. Thesereactive derivatives can optionally be selected from them according tothe kind of the compound (II) to be used.

In this reaction, compound (III) or a salt thereof is reacted withcompound (II) or a reactive derivative at the carboxy group or a saltthereof, to form a mixed acid anhydride of compounds (III) and (II),which is then is decarbonated to form compound (I).

In this reaction, however, compound (III) may be decarbonated dependingon reaction conditions to form the following compound:

, with which compound (II) or a reactive derivative at the carboxy groupor a salt thereof reacts, thus giving compound (I). This reaction isalso encompassed by the process of this invention.

The process is carried out in a conventional solvent such as dioxane,chloroform, methylene chloride, tetrahydrofuran or any otherconventional solvent which does not adversely influence the reaction.

When the compound (II) is used in a free acid form or its salt form inthe reaction, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N′-dicyclohexylcarbodiimide,N-cyclohexyl-N′-morpholinoethylcarbodiimide,N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, thionyl chloride, oxalylchloride, lower alkoxycarbonyl halide (e.g. ethyl chloroformate,isobutyl chloformate, etc.),1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, or the like.

The reaction temperature is not critical and the reaction is usuallycarried out at ambient temperature or under heating.

PROCESS 2

In this reaction, compound (IV) or a salt thereof is reacted in step 1with hypochlorite or hypobromite to form the following compound:

or a salt thereof or the following compound:

or a salt thereof, and this product may be isolated and then reacted instep 2 with compound (II) or a reactive derivative at the carboxy groupor with a salt thereof, to give compound (I) or a salt thereof, or saidproduct may, without being isolated, be reacted with compound (II) or areactive derivative at the carboxy group or with a salt thereof. Eachcase is encompassed by the process of the present invention.

Preferable examples of hypochlorite and hypobromite include a salt withalkali metal (sodium, potassium, etc.) or with alkaline earth metal(calcium etc.).

Because step 1 proceeds in a known reaction form as Hofmannrearrangement, the reaction reagents and reaction conditions (e.g.,solvent, reaction temperature, etc.) include those known to cause theHofmann rearrangement.

Suitable reaction solvent in the reaction of step 1 is water. Thereaction temperature is not critical and the reaction is preferablycarried out at ambient temperature or under heating.

The reaction of step 2 can be carried out in substantially the samemanner as above process 1, therefore reaction reagent and reactioncondition (e.g. solvent, reaction temperature, etc.) described inprocess 1 may be used.

The compounds obtained by the above processes can be isolated andpurified by a conventional method such as pulverization,recrystallization, column chromatography, reprecipitation, or the like.

The compound (I) and other compounds may include more than one opticalisomer due to asymmetric carbon atom(s). The isomer and mixture thereofmay be included in the scope of the invention.

Further, the hydrate of compound (I) may be included in the scope of theinvention.

The object compound (I) and pharmaceutically acceptable salts thereofpossess a strong potentiation of the cholinergic activity and they areuseful for treating disorders in the central nervous system, especiallyfor treating amnesia, dementia, senile dementia, and the like in humanbeing.

One object of the present invention is to provide the new processes forpreparing the compound (I) or a salt thereof as described above.

The present invention is based on finding that the processes forpreparing the object compound (I) and sals thereof are superior to theknown processes in point of yield and purity, and further in point of aless number of steps with a synthetic pathway without proceeding vianitroso compounds.

The following Preparations and Examples are given for the purpose ofillustrating the present invention in more detail, and don't restrictthe scope of the invention.

PREPARATION 1

N-Acetylpiperazine (25.0 g) was added to water (100 ml) and dissolvedunder stirring at ambient temperature. Then, the solution was adjustedto pH 3.0 with 6 N hydrochloric acid (about 33 ml). After the solutionwas cooled, sodium isocyanate (15.2 g) was added in one portion theretoat a temperature of 5 to 10° C. Thereafter, the mixture was reacted for4 hours at ambient temperature and then cooled on ice to −2 to 2° C. Themixture was stirred at the same temperature for 2 hours to precipitate4-acetyl-1-piperazinecarboxamide crystals. The crystals were collectedat the same temperature by filtration, washed with cold water (25 ml)and dried under reduced pressure to give primary crystals of4-acetyl-1-piperazinecarboxamide (17.7 g). The mother liquor containingthe primary crystals was concentrated to 63 ml under reduced pressureand then stirred at −2 to 2° C. for 2 hours to precipitate secondarycrystals of 4-acetyl-1-pipeazinecarboxamide. The crystals were collectedat the same temperature by filtration, washed with cold water (13 ml)and dried under reduced pressure to give secondary crystals of4-acetyl-1-piperazinecarboxamide (9.3 g). NMR (DMSO-d6, δ): 2.00 (3H,s), 3.21-3.41 (8H, m), 6.04 (2H, Broad s)

EXAMPLE 1

1 N Aqueous sodium hydroxide (70 ml) and water (30 ml) were cooled at 5to 10° C., and 4-acetyl-1-piperazinecarboxamide (10.0 g) was addedthereto and dissolved under stirring. 10% Aqueous sodium hypochlorite(43.5 ml) was added in one portion thereto at the same temperature andallowed to react for 1 hour at the same temperature, and after thetemperature was raised, the mixture was further reacted for 2 hours at atemperature of 15 to 20° C. The reaction solution containing4-acetyl-1-piperazinylcarbamic acid was adjusted to pH 6.5-7.5 with 1 Nhydrochloric acid (about 23 ml), followed by adding tetrahydrofuran (100ml). A solution of 4-fluorobenzoyl chloride (11.1 g) in tetrahydrofuran(20 ml) was added dropwise thereto at 20 to 30° C. over the period of 1hour. Because the pH was decreased during the addition, the reactionsolution was kept at pH 6.0 to 7.0 with 1 N aqueous sodium hydroxide.After this dropwise addition was finished, the solution was furtherreacted for 2 hours at the same temperature and at the same pH. Thereaction solution was concentrated to 50 ml under reduced pressure, thencooled on ice and stirred at 5 to 10° C. for 1 hour to precipitateN-(4-acetyl-1-piperazinyl)-4-fluorobenzamide. The resultant crystalswere collected at the same temperature by filtration, washed with coldwater (50 ml) and dried under reduced pressure to giveN-(4-acetyl-1-piperazinyl)-4-fluorobenzamide (8.35 g). NMR (DMSO-d6, δ):2.03 (3H, s), 2.77-2.92 (4H, m), 3.50-3.52 (4H, m), 7.23-7.34 (2H, m),7.82-7.89 (2H, m), 9.58 (1H, s)

What is claimed is:
 1. A process for the preparation of a compound ofthe formula:

or a salt thereof which comprises reacting a compound of the formula:

or a salt thereof with a compound of the formula:

or its reactive derivative at the carboxy group or a salt thereof,wherein R¹ is lower alkyl, aryl, ar(lower)alkoxy or a thienyl group,each of which may be substituted with halogen, and R² iscyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may besubstituted with halogen.
 2. A process for the preparation of a compoundof the formula:

or a salt thereof which comprises reacting a compound of the formula:

or a salt thereof with a hypochlorite or a hypobromite and then reactingthe compound obtained or a salt thereof with a compound of the formula:

or its reactive derivative at the carboxy group or a salt thereof,wherein R¹ is lower alkyl, aryl, ar(lower)alkoxy or a thienyl group,each of which may be substituted with halogen, and R² iscyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may besubstituted with halogen.